TY - JOUR
T1 - Regulation of vascular contractility and blood pressure by the E2F2 transcription factor
AU - Zhou, Junlan
AU - Zhu, Yan
AU - Cheng, Min
AU - Dinesh, Deepika
AU - Thorne, Tina
AU - Poh, Kian Keong
AU - Liu, Dongxu
AU - Botros, Chantal
AU - Tang, Yao Liang
AU - Reisdorph, Nichole
AU - Kishore, Raj
AU - Losordo, Douglas W.
AU - Qin, Gangjian
PY - 2009/9
Y1 - 2009/9
N2 - BACKGROUND-: Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation. METHODS AND RESULTS-: Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2 mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2 mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a,-1c, and-1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays). CONCLUSION-: Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.
AB - BACKGROUND-: Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation. METHODS AND RESULTS-: Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2 mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2 mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a,-1c, and-1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays). CONCLUSION-: Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.
KW - Blood pressure
KW - E2F transcription factors
KW - Endothelin
KW - Endothelium
KW - Mouse
KW - Sam68 protein
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UR - http://www.scopus.com/inward/citedby.url?scp=70349661885&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.109.859207
DO - 10.1161/CIRCULATIONAHA.109.859207
M3 - Article
C2 - 19752322
AN - SCOPUS:70349661885
SN - 0009-7322
VL - 120
SP - 1213
EP - 1221
JO - Circulation
JF - Circulation
IS - 13
ER -